New classes of antiretroviral agents effective against both wild-type and drug-resistant variants of HIV-1 will provide urgently needed therapeutic options for a growing number of AIDS patients harboring HIV-1 that is resistant to currently approved antiretroviral drugs. Phosphonoformic acid (PFA) is a broad-spectrum antiviral drug that inhibits the HIV-1 reverse transcriptase (RT) through a different mechanism than nucleoside RT inhibitors (NRTI's), but which has not been developed for treatment of HIV infection because of modest potency, poor oral availability and toxicity resulting from the high plasma levels required to achieve antiviral activity. Alkylglycerol analogs of PFA may address the limitations of PFA as a treatment for drug resistant HIV-1 infection. Some of these analogs exhibit enhanced antiviral activity in cell culture assays and greater oral availability in mice compared with unmodified PFA. The ability to administer PFA analogs orally and to address dose-limiting toxicities of PFA by reducing both the concentration and anionic nature of the drug in plasma and kidneys suggests that these analogs may be suitable drug candidates for the treatment of multidrug resistant HIV-1 infection. The overall objective of this proposal is to identify an optimized alkylglycerol PFA analog that is suitable for formal preclinical development leading to submission of an IND for phase I clinical trials. Specific Aims of this phase I SBIR proposal are as follows: 1) Determine which medicinal chemistry parameters of alkylglycerol PFA analogs most profoundly affect antiviral potency and selectivity in cell culture assays; 2) Determine which medicinal chemistry parameters of alkylglycerol PFA analogs most profoundly affect oral availability in rodents; 3) Compare toxicokinetic parameters of at least 2 lead compounds in 14-day dose range finding toxicity studies in mice; 4) Compare the ability of lead compounds to reduce circulating HIV-1 levels after oral dosing in a SCID-hu murine model of HIV-1 infection; and 5) Designate one alkylglycerol PFA analog as a drug candidate suitable for preclinical studies that will enable filing of an Investigational New Drug (IND) application and Phase I clinical trials.